Blog

The COVID-19 pandemic has created a global call to action to pharmaceutical companies for the development of a suitable vaccine. In the development of such vaccine(s), understanding the biostability and kinetics/thermodynamics of very small and dilute protein solutions is necessary. Thermal stability is important for the performance of proteins and other biostructures within vaccines. Denaturing of protein structure can limit vaccine function and thus reduce effectiveness of any developed vaccine within the pharmaceutical sector.

Micro DSC 7

C-Therm Technologies Ltd. has worked closely with the world-leader in calorimetry, Setaram Instrumentation, for over a decade. With the SETARAM µDSC VII (See Figure 1) equipped with the unique Calvet sensor’s 93-95% heat detection efficiency, small and precise thermodynamic events can be observed at nanomolar concentrations. Compared to traditional pan-style calorimetry instrumentation, the 3D Calvet sensor offers substantially better sensitivity for the purpose of studying vaccine formulations, or thermal stability of finalized products. With increased urgency in the development of a vaccine for COVID-19, the µDSC VII and µSC DSC instrumentation offer flexibility to measure solids, liquids, solutions and more. Different sample cells can provide mixing, or standard isothermal measurement runs, perfect for monitoring enzymatic reactions in kinetic or isothermal measurement modes. Additionally, the µSC DSC offers higher capacity for running multiple samples at the same time, allowing for comparison between different formulations for vaccine or other biomolecule solutions. Compared to other pan style or capillary style DSC instruments, SETARAMs calorimetry offerings provide versatility without compromising sensitivity and have become a benchmark tool for studying thermal stability of vaccine formulations within the pharmaceutical sector.

Internal Cell of Micro DSC 7

C-Therm is offering access to its Setaram calorimeter via its lab services in support of research organizations developing COVID-19 vaccines and can lend considerable expertise in outfitting labs with the high sensitivity tools for accelerating the development of vaccines.

Understanding the fundamental thermal properties of a given material is an important aspect of material design and study. Tools to explore a material’s thermal properties include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and differential thermal analysis (DTA). TGA measures weight change of a sample over a temperature range, DSC measures heat flow of a sample over a temperature range, and DTA measures heat differences between a reference sample and a sample of interest over a temperature range. From these individual techniques, we can determine heat capacity, glass transition points, crystallinity data, and thermal stability of a material.

All three methods are available through TAL with Setaram’s Labsys Evo system.

Thermogravimetric Analysis (TGA)

TGA is a
powerful and robust technique to explore the thermal stability of a material. By
accurately monitoring the weight of a sample while heating at a constant rate,
we can measure changes in a sample’s weight and attribute this to a specific material
response to a thermal stress (Figure 1). This is perfect for exploring,
in detail, decomposition temperatures and ensuring a material performs
adequately in a given temperature range.

During a test, a
carrier gas flows over the sample and the weighing mechanism. This carrier gas serves two purposes:
protecting the internals from corrosion/oxidation above 500 °C, and to interact with the sample through gas-solid or gas-liquid
reactions. By providing an inert atmosphere, we can test the thermal stability
of a material. Reducing environments can explore gas-solid phase reduction
reactions or protect specific samples from being oxidized. By the nature of the
sensitivity of the TGA balance, we also can observe the absorption of gas onto
a porous material at various temperatures. This is an ideal technique for
exploring metal organic frameworks, or catalytic porous materials. Owing to the
sensitivity of the balance on our SETARAM Labsys Evo instrument, we have ideal
sensitivity for running thermokinetic experiments. This experiment has
applications towards thermal stability of a given material at elevated
temperatures.

The SETARAM Labsys offers the ability to perform TGA analysis up to 1600 °C and additionally under a variety of gas mixtures due to our gas-mixing option.

Differential Scanning Calorimetry (DSC)

DSC is a flexible technique to explore thermal transitions within a given sample. By heating a sample and measuring the heat flow as compared to a reference standard, we can access thermoanalytical information on a given material. DSC curves are generated by plotting heat flow (mW) vs sample temperature (°C), and an example plot is found in Figure 2, and demonstrates the melting and fusion of Indium Corp. Indalloy 80Au/20Sn solder. In this case, we observe a phase change (solid-liquid followed by liquid-solid); however, we can also observe other thermal transitions within a material, such as evaporation, thermal transitions between polymorphs, and determination of key thermal constants. One of these key thermal constants is heat capacity (Cp), which an be difficult to acquire due to the demanding experiment required to gain access to this information. Heat capacity requires precise and very specific sensitivity of the DSC sensor, as it is a very small and difficult thermal effect to capture effectively. Owing to our 3D Calvet type sensor on our µDSC 7, we have the capability to measure such small thermal effects (0.02 µW) requiring the upmost sensitivity and precision from 0 – 120 °C. For higher temperatures, our SETARAM Labsys Evo instrument has a specifically designed 3D-psuedo-Calvet sensor, which allows TAL to perform Cp testing with better than 2% accuracy from ambient temperatures to 1600 °C. This very sensitive and difficult to determine thermal effects also include the glass transition point (Tg), water state in materials and other thermodynamic and thermokinetic effects.

Figure 2: (main) A thermogram demonstrating the melting point of a common solder at 280.782 °C as compared to its literature point of 280 °C. The melting point is determined using the ISO 11357-3 standard definition. (inset): A picture of the internals of our DSC 7, showing a sample and its reference during a DSC experiment.

Differential Thermal Analysis (DTA)

DTA is a similar technique to DSC, however instead of measuring the heat flow between the furnace temperature and the sample, you measure the temperature difference between a sample and a standard reference using thermocouples. This is particularly useful for phase-change materials and the study of organic and polymeric materials using analytical precision. Owing to the more sensitive detector within typical DTA sensors, DTA testing is particularly useful for running thermokinetic experiments due to the lower thermal inertial barrier. TAL offers DTA testing from ambient to 1200 °C, allowing us to explore thermal effects at elevated temperature, capabilities which we have newly acquired.

Figure 3: A thermogram showing two experimental curves of the decomposition of CuSO4•5H2O, a TGA standard. TGA (blue curve) thermogram shows the loss of 5 water (36 wt%). Each loss of water corresponds to an endotherm signal (DSC, orange), which would be expected for the loss of water from CuSO4•5H2O.

While each of these techniques may be used to probe into a single physical characteristic of a material, the real power we provide is simultaneous thermal analysis techniques for niche applications on a single sample. With TAL’s Labsys Evo 1600 and DSC 131, we offer capabilities to include high temperature ranges with mixtures of gases. For example, TAL offers TGA, DSC and DTA experiments from ambient temperatures up to 1600 °C. Figure 3 shows a TGA-DSC decomposition experiment captured on our Setaram Labsys Evo apparatus, where CuSO4•5H2O decomposition can be measured by TGA (water, SO2 and O2) and DSC. In addition to these coupled thermal experiments, we offer the capacity to provide gas mixtures for high precision control over the exact atmospheric exposure during thermal analysis runs. TAL also offers the capacity to run samples under vacuum (10-3 Bar) using our Labsys Evo system, which is useful for isolating gas-sample interactions. TAL also offers pressurized DSC experimentation, allowing for the study of various samples under 200 psi. This can provide insight into thermal transitions under pressure, such as those in the oil and fuel industry or in the case of high-pressure lubricants. Additionally, we have access to specialized high pressure self-sealed cells, allowing for the study of close-system up to 500 bar and 500 °C. Below is a summary of our newest expanded capabilities (Table 1):

Table 1: Newly acquired techniques available for TAL. Each technique is followed by the constraints of our analysis. In the case of gases, TAL can work with the client to explore other gas opportunities.

*Liquid vapour pressure, not controlled.

With significant
investment into these powerful thermal analysis instruments, TAL offers broad
capacity to serve our clients with some of the most relevant thermal analysis tools.
With our expertise in thermal analysis, we offer solutions to research and
materials questions and are here to provide our customers with the best support
in their thermal analysis needs. Feel free to chat with us about our contract
testing services and we will find a solution that best suits your needs.

Phase change materials (PCMs) are substances with a high latent heat (typically of fusion) which may be used to store a large degree of heat energy by melting and crystallizing at a certain temperature. PCMs can be organic, inorganic, eutectics, and hydroscopics (where the phase change is not a change of fusion but rather of absorption and desorption of water vapor). A key performance metric of a PCM is its ability to exchange heat with its surroundings – a metric which is often referred to as “thermal inertia” or, more commonly, “thermal effusivity.” A higher thermal effusivity allows a material to be thermally activated in a more rapid manner – and therefore more thermal load can be stored during a dynamic thermal process. In short: PCMs with higher thermal effusivity can absorb or release more thermal energy, faster.

Thermal effusivity is governed by the following equation:

e = (k p Cp)1/2

Where e is the thermal effusivity, p (rho) is density, Cp is the mass specific heat capacity at constant pressure, and k is the thermal conductivity. Thermal effusivity may be expressed equivalently in units of Ws1/2/m2K or J/s1/2m2K.

How thermal effusivity describes the ability of a material to exchange heat with its surroundings is a large part of why not only k is important to PCM performance, but also the volumetric heat capacity, or . Given density information as a function of temperature, thermal conductivity information as a function of temperature, and a DSC curve which provides specific heat data, it is possible to calculate the thermal effusivity of a material as a function of temperature, which Korean scientists recently did in a paper published in the Journal of Adhesion Science and Technology. Their results are seen above in Figure 1.

However, this approach may be difficult, as it is often hard to obtain accurate density and thermal conductivity data during a phase transition – which can introduce error to the process and is time-consuming as it requires collection of thermal expansion and thermal conductivity data as well as DSC data. Researchers are increasingly benefitting from the ability to directly measure the thermal effusivity instead of calculating it – and thus reduce the error introduced by assumptions of constant density or thermal conductivity.

The C-Therm TCi Thermal Conductivity Analyzer is primarily known for its ability to measure the thermal conductivity of materials – however, it also directly measures the thermal effusivity of materials. It is compliant with existing standards for the measurement of thermal effusivity via the Modified Transient Plane Source method (ASTM Standard D7984).

A sample of paraffin wax, a commonly used base for many organic phase-change materials, was obtained and its thermal effusivity was monitored as a function of temperature on cooling through the phase change. The resulting data is plotted below in Figure 2:

Figure 2. Measured thermal effusivity of paraffin as a function of temperature

At the highest point, the measured thermal effusivity is 1.49 x 103 Ws1/2/m2K. Aside from the phase transition highlighted in pink, the data plotted also exhibits a peak near 40°C and another near 22°C – it is fairly common for paraffins to exhibit crystal-crystal transitions in the latter, and the former is explainable by the melt of a minor component with a shorter chain length than the bulk of the wax. The performance of paraffin in this metric is best illustrated by comparison to the results obtained by the Korean group, whose shape-stabilized PCM exhibited a thermal effusivity at its peak of 103.19 x 103 Ws1/2/m2K – nearly two full orders of magnitude larger. As expected from the well-known thermal performance issues of pure paraffin in phase-change applications, this suggests that paraffin has difficulty exchanging heat with its surroundings, which limits its utility as a PCM.

Thermal interface materials (TIMs) are widely used to reduce thermal resistance at the interface between two materials (often called the thermal contact resistance). There are many different types of TIMs, ranging from thermal greases to thermal glues, thermal gap pads, and thermal adhesive pads. Of these, thermal greases (Figure 1) are popular because they tend to be easy-to-use, non-toxic, and non-permanent solutions to the thermal contact resistance problem.

Thermal greases are difficult for many traditional methods of thermal conductivity testing to analyze: They are highly viscous, resulting in a very slow pour rate. As a result, air can become entrapped within the material and artificially deflate its thermal conductivity.

The unique planar, one-sided and one-directional thermal conductivity measurement provided by the C-Therm TCi Thermal Conductivity Analyzer provides a useful tool for the performance verification of thermal grease compounds, as the grease may be applied directly to the sensor surface, minimizing the formation of bubbles and enabling a uniform sample distribution over the sensor. Additionally, the small sensor surface area, short test time, and the optional small volume test kit result in a very small sample volume (< 2 mL) required to obtain good data, reducing the wastage in quality-control applications and the synthetic demand in research applications.

Figure 2. Thermal Conductivity Testing of a Thermal Grease

The C-Therm TCi Thermal Conductivity Analyzer was used to test the thermal conductivity of a thermal grease compound. The observed value was referenced to the manufacturer’s specification for the grease’s thermal conductivity performance. The grease was found to test within 2% of the manufacturer’s specification on all tests. The mean of three tests of five measurements each was 0.727 W/mK. The relative precision for each of the three tests was 0.4%, 0.3%, and 0.2%, respectively, and the relative standard deviation across the three tests was 0.5%.

Aerogels are a relatively new class of ultralight, porous materials, typically derived from a gel. In an aerogel, the liquid component of the gel has been replaced by a gas (typically air). Owing to the very light nature of most aerogels, most aerogel samples have a transluscent, blueish appearance. Porosity of aerogels is generally in excess of 98% (meaning that, per unit volume, >98% of an aerogel’s volume is pore volume). Aerogels can be made of a variety of chemical compounds.

Image Source: NASA/JPL-Caltech

Aerogels (above) are known for their extremely low thermal conductivity, which is often lower than that of air. In this respect, the thermal conductivity of an aerogel material is typically identified as a critical performance specification. This low thermal conductivity makes aerogel materials exciting in the field of insulation research, where engineers are continually looking to improve energy efficiency without adding excessive weight.

It can be seen that the thermal conductivity performance measured is in good agreement with the specified thermal conductivity of these commercially-available aerogel samples. Agreement with the specified value in all three cases was better than 4%.

Increasingly, work is being devoted to replacing heavy and expensive metallic heat sinks with lower cost, lighter organic-based heat sinks. One way in which to do this is to mix a polymer material with some thermally conductive additive to improve its thermal conductivity. Such a material is referred to as a thermally-conductive polymer composite (TCPC) material. The field of TCPC research is an emerging and highly competitive one – however, historically, such materials have historically possessed very high percolation thresholds – the percolation threshold being the point at which an additive in such a mixture begins to have an appreciable and scalable effect upon the thermal conductivity of the mixture, before which there is little, if any appreciable improvement in thermal conductivity upon successive additions of additive (Figure 1).

As a result of the high percolation threshold, very high loadings of additives (30 wt% or more) have been needed to achieve the desired thermal conductivity. The issue with such a high loading is that it sacrifices the mechanical properties, and sometimes the electrical properties, of the composite for the thermal conductivity, and it makes the composite denser, resulting in a heavier consumer good. Research in recent years has therefore focused on ways of reducing the required additive loading.

A key finding of their work is summarized in Figure 1. With a C-Therm TCi Thermal Conductivity Analyzer, Huang et al were able to study the effect of graphite content on the various polymer blends. The graphene loading improves the thermal conductivity of the PLA and PCL, but only marginally. However, once it becomes trapped at the interface of the polymer blend, the thermal conductivity of the material substantially improves, resulting in a four-fold improvement of the thermal conductivity of the material with merely a 0.5 volume % doping of graphene into the material. Remarkably, the percolation threshold of the PCL/PLA/GE blend (circled) was 0.11 vol%, representing the lowest percolation threshold for TCPC yet discovered.

Polyethylene Terathalate (PET or PETE), is among the most used types of plastics in industry. It is used in drink and frozen food packaging and as a synthetic fibre under the common name “polyester.” As a result of its wide application, particularly in food applications, strict quality control is needed over batches. Measurement of glass transition temperature is one way in which quality of a batch of PET may be assessed.

Glass transition temperature (Tg) is a characteristic of some amorphous materials, including plastics. At the glass transition temperature, the material converts from a hard and brittle “glassy” state to a soft and rubbery, semi-molten state. At temperatures above this point, the plastic has a compromised ability to retain form and structure, unless it undergoes a recrystallization at a higher temperature. A literature survey for PET’s glass transition temperature shows it to be between 69°C and 85°C, depending on the grade examined.1 The C-Therm Dilatometer (DiL), which uses a horizontal Linear Variable Displacement Transducer (LVDT)-based technology compliant to ASTM E228 can be used to observe this phenomenon.

Figure 1. C-Therm DiL High Precision Dilatometer

The glass transition of a polymer is evident via dilatometry as an inflection point in the thermal expansion curve, in between two regions of linear thermal expansion – the exact temperature of the transition is then determined using the two-line method. For added convenience, consistency and confidence, an advanced software package such as CALISTO data processing software may be used to automate analysis of the Tg point, thus eliminating possible user bias.

Measurement of Glass Transition Temperature
A 50mm piece of PET was cut from a thin rod, and the end surfaces were polished to achieve a smooth contact between the sample and the pushrod. A tipped pushrod was used with a cross-sectional area of 1 mm2. The minimal force employable by the DiL was used upon the sample to minimize contact force and reduce the risk of sample deformation.

The operation of the dilatometer was conducted in compliance with known measurement standards for thermal analysis.2 When thermally analyzing thermoplastics, one must be mindful of the effect of thermal history of the sample. This may be addressed by pre-conditioning the sample at a temperature above its glass transition temperature, taking care not to exceed the dilatometric softening point or recrystallization temperature, depending on the thermoplastic in question. The heating rate should not exceed 5°C/min. This preconditioning process normalizes the thermal history of the sample, enabling repeatable data collection. The measurement may then be conducted either upon the cooling from the temperature above the glass transition temperature, or with a second heating cycle.

PET is a material which is widely known to have morphology and thermal properties which are sensitive to its thermal history. Therefore, for this work, the sample was allowed to soak for 30 minutes at this 30°C to normalize the initial condition of the measurements. The sample was then heated at a rate of 5°C/min to 130°C then cooled. Measurement was conducted on the cooling cycle. The resulting measurement profile on the cooling part was obtained and analyzed using the Calisto software. Figure 2 shows the profile obtained and the glass transition temperatures on the first test.

The repeatability is remarkable with an RSD of 0.7%. The average of the two measurements, at 75.35°C falls well within the expected range of 69°C-80°C.

In conclusion, glass transition temperature can be measured in a repeatable manner using horizontal pushrod dilatometry, provided the thermal memory of the sample is normalized through the heating profile.